Impact of accessory gene regulator (agr) dysfunction on vancomycin pharmacodynamics among Canadian community and health-care associated methicillin-resistant Staphylococcus aureus

40 clinical isolates of MRSA from the Canadian Nosocomial Infection Surveillance Program were evaluated for delta-haemolysin production, as a surrogate marker of agr function. Time kill experiments were performed for vancomycin at 0 to 64 times the MIC against an initial inoculum of 106 and 108 cfu/ml of agr functional and dysfunctional CA-MRSA and HA-MRSA and these data were fit to a hill-type pharmacodynamic model.15% isolates were agr dysfunctional, which was higher among HA-MRSA (26.3%) versus CA-MRSA (4.76%). Against a low initial inoculum of 106 cfu/ml of CA-MRSA, vancomycin pharmacodynamics were similar among agr functional and dysfunctional strains. However, against a high initial inoculum of 108 cfu/ml, killing activity was notably attenuated against agr dysfunctional CA-MRSA (USA400) and HA-MRSA (USA100). CA-MRSA displayed a 20.0 fold decrease in the maximal reduction in bacterial counts (Emax) which was 3.71 log10 CFU/ml for agr functional vs. 2.41 log10 CFU/ml for agr dysfunctional MRSA (p = 0.0007).Dysfunction in agr was less common among CA-MRSA vs. HA-MRSA. agr dysfunction demonstrated an impact on vancomycin bactericidal activity and pharmacodynamics against a high initial inoculum of CA-MRSA and HA-MRSA, which may have implications for optimal antimicrobial therapy against persistent, difficult to treat MRSA infections.The accessory gene regulator (agr) is a quorum sensing cluster of genes which orchestrate the expression of cell-secreted and virulence factors, and several metabolic pathways in Staphylococcus aureus in a growth dependant fashion [1,2]. It has been hypothesized that S. aureus which exhibit agr dysfunction may possess an intrinsic survival advantage: these strains have demonstrated vancomycin tolerance and a proclivity to develop heterogeneous resistance under vancomycin selective pressure[3,4]. However, agr dysfunction has primarily been evaluated in strains of healthcare-associated (HA) MRSA where a down-regulated agr locus has been